Interleukin-17 is a negative regulator of established allergic asthma

T helper (Th)17 cells producing interleukin (IL)-17 play a role in autoimmune and allergic inflammation. Here, we show that IL-23 induces IL-17 in the lung and IL-17 is required during antigen sensitization to develop allergic asthma, as shown in IL-17R–deficient mice. Since IL-17 expression increased further upon antigen challenge, we addressed its function in the effector phase. Most strikingly, neutralization of IL-17 augmented the allergic response in sensitized mice. Conversely, exogenous IL-17 reduced pulmonary eosinophil recruitment and bronchial hyperreactivity, demonstrating a novel regulatory role of IL-17. Mechanistically, IL-17 down modulated eosinophil-chemokine eotaxin (CCL11) and thymus- and activation-regulated chemokine/CCL17 (TARC) in lungs in vivo and ex vivo upon antigen restimulation. In vitro, IL-17 reduced TARC production in dendritic cells (DCs)—the major source of TARC—and antigen uptake by DCs and IL-5 and IL-13 production in regional lymph nodes. Furthermore, IL-17 is regulated in an IL-4–dependent manner since mice deficient for IL-4Rα signaling showed a marked increase in IL-17 concentration with inhibited eosinophil recruitment. Therefore, endogenous IL-17 is controlled by IL-4 and has a dual role. Although it is essential during antigen sensitization to establish allergic asthma, in sensitized mice IL-17 attenuates the allergic response by inhibiting DCs and chemokine synthesis

Role of IL-1β in experimental cystic fibrosis upon P. aeruginosa Infection

Cystic fibrosis is associated with increased inflammatory responses to pathogen challenge. Here we revisited the role of IL-1β in lung pathology using the experimental F508del-CFTR murine model on C57BL/6 genetic background (Cftrtm1eur or d/d), on double deficient for d/d and type 1 interleukin-1 receptor (d/d X IL-1R1-/-), and antibody neutralization. At steady state, young adult d/d mice did not show any signs of spontaneous lung inflammation. However, IL-1R1 deficiency conferred partial protection to repeated P. aeruginosa endotoxins/LPS lung instillation in d/d mice, as 50% of d/d mice succumbed to inflammation, whereas all d/d x IL-1R1-/- double mutants survived with lower initial weight loss and less pulmonary collagen and mucus production, suggesting that the absence of IL-1R1 signaling is protective in d/d mice in LPS-induced lung damage. Using P. aeruginosa acute lung infection we found heightened neutrophil recruitment in d/d mice with higher epithelial damage, increased bacterial load in BALF, and augmented IL-1β and TNF-α in parenchyma as compared to WT mice. Thus, F508del-CFTR mice show enhanced IL-1β signaling in response to P. aeruginosa. IL-1β antibody neutralization had no effect on lung homeostasis in either d/d or WT mice, however P. aeruginosa induced lung inflammation and bacterial load were diminished by IL-1β antibody neutralization. In conclusion, enhanced susceptibility to P. aeruginosa in d/d mice correlates with an excessive inflammation and with increased IL-1β production and reduced bacterial clearance. Further, we show that neutralization of IL-1β in d/d mice through the double mutation d/d x IL-1R1-/- and in WT via antibody neutralization attenuates inflammation. This supports the notion that intervention in the IL-1R1/IL-1β pathway may be detrimental in CF patients

Effects of Nintedanib in an Animal Model of Liver Fibrosis

Systemic sclerosis can affect multiple internal organs, including the liver and lungs. Nintedanib, an antifibrotic approved for treatment of interstitial lung disease associated with systemic sclerosis, may have activity outside of the lungs. This study explored the effect of preventive and therapeutic nintedanib treatment in a 3-week carbon tetrachloride (CCL4)-induced (500 mg/kg/day twice weekly for 3 weeks) model of hepatic inflammation and fibrosis in C57Bl/6 mice (aged 8 weeks, n=5 per group). Mice also received nintedanib (30 or 60 mg/kg/day) either each day for 21 days (preventive treatment) or from day 7 or day 14 (therapeutic treatment). Preventive nintedanib treatment at both doses significantly reduced CCL4-induced increases in myeloperoxidase (p<0.01), hepatic collagen (p<0.001), and interleukin (IL)-6 (p<0.01) in the liver. Nintedanib also significantly reduced hepatic necrosis (p<0.01 and p<0.05), inflammation (p<0.001 and p<0.05), fibrosis (p<0.001 and p<0.05) and IL-1β (p<0.05 and p<0.001) at both 30 and 60 mg/kg/day, respectively. Therapeutic treatment with nintedanib at 30 and 60 mg/kg/day significantly reduced CCL4-induced serum alanine aminotransferase from day 7 (p<0.05 and p<0.001) and day 14 (p<0.01 and p<0.05), respectively. Increases in tissue inhibitor of metalloproteinase-1 were significantly reduced by nintedanib at 60 mg/kg/day from day 7 only (p<0.001), and nintedanib completely blocked elevation of IL-6 and IL-1β levels regardless of dose or start of treatment (p<0.05–p<0.001). In both the preventive and therapeutic treatment schedules of the study, nintedanib treatment was beneficial in attenuating CCL4-induced pathology and reducing hepatic injury, inflammation, and fibrosis, demonstrating that nintedanib has antifibrotic and anti-inflammatory activity outside of the lungs

Récepteurs Toll (TLRs) et leurs voies de signalisation (rôles dans les réponses innée et acquise aux antigènes de la tuberculose et du paludisme (malaria))

Les maladies infectieuses sont responsables de 14 millions de décès chaque année dans le monde. La reconnaissance des motifs structuraux des pathogènes se fait par l intermédiaire de récepteurs dont les "Toll-like" ou TLRs. Les TLRs et leurs molécules adaptatrices sont des composants fondamentaux de l'immunité innée. Cette étude vise à comprendre le rôle des TLRs, de leurs voies de signalisation et de certaines cytokines induites dans les réponses immunitaires mises en œuvre dans les modèles de maladies infectieuses comme la malaria cérébrale, la tuberculose, l asthme allergique et non allergique. L analyse est réalisée chez les souris génétiquement déficientes pour différents TLRs, les molécules adaptatrices MyD88, TIRAP, et TRIF ainsi que les molécules de la famille du TNF. Cette étude a permis de montrer que la voie de signalisation impliquant TLR4, MyD88 et TIRAP est essentielle, alors que les voies impliquant TRIF ou IL-1R1 et IL-18R ne sont pas indispensables à l inflammation des voies respiratoires induite par le LPS. Dans le modèle d infection par Plasmodium berghei Anka, ni les TLRs, MyD88, TIRAP, ou TRIF ne sont impliqués dans la pathogenèse de la malaria cérébrale. Nous avons également mis en évidence le rôle majeur joué par LTa, LTb et les voies de signalisation impliquant TNFR2 et LTbR dans la malaria cérébrale. Finalement, dans le modèle d infection à Mycobactérium tuberculosis, au-delà des voies TLRs, la voie IL-1R1 dépendante de MyD88 est essentielle pour le contrôle de l infection aigue.ORLEANS-BU Sciences (452342104) / SudocSudocFranceF

The Micro-Immunotherapy Medicine 2LEID Exhibits an Immunostimulant Effect by Boosting Both Innate and Adaptive Immune Responses

This study aimed at evaluating the effects of the micro-immunotherapy medicine (MIM) 2LEID, both in vitro and in vivo, on several components of the innate and adaptive immune system. MIM increased the phagocytic activity of macrophages, and it augmented the expression of the activation markers CD69 and HLA-DR in NK cells and monocytes/macrophages, respectively. The effect of MIM was evaluated in a model of respiratory infection induced by influenza A virus administration to immunocompetent mice in which it was able to improve neutrophil recruitment within the lungs (p = 0.1051) and slightly increased the circulating levels of IgM (p = 0.1655). Furthermore, MIM stimulated the proliferation of CD3-primed T lymphocytes and decreased the secretion of the immunosuppressive cytokine IL-10 in CD14+-derived macrophages. Human umbilical vein endothelial cells were finally used to explore the effect of MIM on endothelial cells, in which it slightly increased the expression of immune-related markers such as HLA-I, CD137L, GITRL, PD-L1 and ICAM-1. In conclusion, the present study suggests that MIM might be a promising nonspecific (without antigen specificity) immunostimulant drug in preventing and early treating respiratory infections, but not only exclusively, as it would gently support several facets of the immune system and host defenses

STING agonist diABZI induces PANoptosis and DNA mediated acute respiratory distress syndrome (ARDS)

International audienceAbstract Stimulator of interferon genes (STING) contributes to immune responses against tumors and may control viral infection including SARS-CoV-2 infection. However, activation of the STING pathway by airway silica or smoke exposure leads to cell death, self-dsDNA release, and STING/type I IFN dependent acute lung inflammation/ARDS. The inflammatory response induced by a synthetic non-nucleotide-based diABZI STING agonist, in comparison to the natural cyclic dinucleotide cGAMP, is unknown. A low dose of diABZI (1 µg by endotracheal route for 3 consecutive days) triggered an acute neutrophilic inflammation, disruption of the respiratory barrier, DNA release with NET formation, PANoptosis cell death, and inflammatory cytokines with type I IFN dependent acute lung inflammation. Downstream upregulation of DNA sensors including cGAS, DDX41, IFI204, as well as NLRP3 and AIM2 inflammasomes, suggested a secondary inflammatory response to dsDNA as a danger signal. DNase I treatment, inhibition of NET formation together with an investigation in gene-deficient mice highlighted extracellular DNA and TLR9, but not cGAS, as central to diABZI-induced neutrophilic response. Therefore, activation of acute cell death with DNA release may lead to ARDS which may be modeled by diABZI. These results show that airway targeting by STING activator as a therapeutic strategy for infection may enhance lung inflammation with severe ARDS

Hippocampal interleukin-33 mediates neuroinflammation-induced cognitive impairments

International audienceBackground: Interleukin (IL)-33 is expressed in a healthy brain and plays a pivotal role in several neuropathologies, as protective or contributing to the development of cerebral diseases associated with cognitive impairments. However, the role of IL-33 in the brain is poorly understood, raising the question of its involvement in immunoregulatory mechanisms

Tenascin-C triggers fibrin accumulation by downregulation of tissue plasminogen activator

We explored novel functions of tenascin-C by comparing mouse embryonic fibroblasts (MEFs) proficient or deficient in tenascin-C expression. Transcript profiling analysis identified tissue plasminogen activator (tPA) as the most consistently over-expressed gene in all tenascin-C deficient MEFs. This was confirmed by real-time PCR as well as by protein expression analysis. In agreement with these observations, tenascin-C deficient MEFs had an increased capacity to digest fibrin in situ. Consistently, tenascin-C expression in vivo was found to correlate with fibrin deposition in several diseases associated with tenascin-C overexpression such as fibrosis, asthma and cancer. In conclusion, the present study suggests a new role of tenascin-C as a regulator of the fibrinolytic system

Experimental atopic dermatitis depends on IL-33R signaling via MyD88 in dendritic cells

International audienc

Aérosolthérapie anti-granulocytaire pour le contrôle des pathologies inflammatoires du poumon

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